CXCR4 and CCR5

Oncogenic and Immunosuppressive Mechanisms of CXCR4

CXCR4 (CXC chemokine receptor 4) is a seven transmembrane G protein-coupled chemokine receptor. Its only endogenous ligand is CXCL12 (CXC chemokine ligand 12, also known as stromal cell-derived factor 1 (SDF-1)). CXCL12 regulates the trafficking of CXCR4+ leukocytes and hematopoetic stem cells under normal physiological conditions (homeostasis). CXCR4 is expressed in T cells, neutrophils, mast cells, eosinophils, basophils, B cells, monocytes/macrophages, dendritic cells, endothelial cells. CXCR4 also plays a crucial role in pathological conditions, such as cancer, HIV/AIDS, and autoimmune diseases.

CXCR4 and CXCL12 stimulate proliferation and migration of hematopoietic stem cells (HSCs) and lineages. The overexpression of CXCR4 on > 48 cancer cell types confers:

  • Pro-survival gene transcription in the primary tumor microenvironment
  • Pro-angiogenic and pro-vasculogenic cytokine expression promoting tumor progression and CXCR4+ cancer cell access to systemic circulation
  • Immunosuppressive and chemo-resistant adhesion to and migration beneath tumor-associated stroma

 

CXCR4 and CXCL12 are independent indicators of poor clinical prognosis for patients suffering from various types of cancer

Oncotarget, Vol 6, No. 7, 2014, 5022-5040.

 

CXCR4 ANTAGONISTS CAN INHIBIT CANCER PROGRESSION BY:

  • Disrupting tumor-associated stromal interactions that confer tumor cell survival and drug resistance
  • Blocking the autocrine and paracrine growth and survival signals through activation of the CXCR4/CXCL12 axis
  • Hindering tumor cell metastasis and homing to distant CXCL12-rich stromal niches
  • Tumor cell mobilization from CXCL12-rich tissue to increase chemotherapeutic accessibility
  • Obstructing CXCL12-mediated recruitment of pro-vasculogenic and pro-angiogenic CXCR4+ bone marrow-derived progenitor cells

CXCR4 inhibitors can also recondition the leukocyte infiltrate of the tumor microenvironment in an immunomodulatory manner that induces a higher susceptibility to the host immune system.

 

 

Development of Dual-tropic HIV-1 Entry Inhibitors

According to UNAIDS, current status on HIV Infections in 2017 shows that 36.9 million people globally were living with HIV; 21.7 million people were accessing antiretroviral therapy; 1.8 million people became newly infected with HIV ; 940 000 people died from AIDS-related illnesses.

Current treatment using Highly Active Antiretroviral therapy (HAART) significantly decreases the mortality of HIV-infected people in industrially developed countries, but is too expensive in low-income and middle-income countries.

 

CXCR4 and CCR5 chemokine receptor blocking inhibits HIV-1 entry and our current research efforts are focused on pan-tropic entry inhibitors.